In the previous period of funding we developed gene transfer vectors based on the herpes simplex virus (HSV) to deliver genes with high efficiency to peripheral sensory neurons. We have exploited this property to develop non-replicating HSV vectors that provide an analgesic effect in models of somatic pain (inflammatory pain, neuropathic pain, and pain resulting from cancer) and visceral pain (bladder inflammation). In this renewal we focus our efforts to further develop HSV vectors for treatment of acute and chronic pain related to diabetes and painful bladder syndromes. Project 1 will explore the use of HSV-mediated transfer of genes that produce inhibitory neurotransmitters (glutamic acid decaraboxylase and proenkephalin) and anti-inflammatory peptides (IL4 and TNFDSR) in models of painful diabetic neuropathy. Project 2 will explore the analgesic effect of these vectors in acute and chronic rodent models of bladder pain. Project 3 will use a vector-based functional genomics approach to identify and characterize novel cellular gene products that inhibit or negatively modulate the activity of the vanilloid receptor TRPV1. Projects 1 and 2 are designed to provide preclinical evidence for vectors that may be developed for novel treatments of human disease, while Project 3 will lead to the identification and evaluation of novel gene products that would then be tested in a similar fashion. Administration (Core A), Preclinical Vector Production (Core B) and Gene Transfer Assays and Imaging (Core C) cores directly support the activities of all three projects. We believe this to be a timely and highly innovative proposal which is likely to provide new approaches to treatment of chronic pain related to diabetes and inflammation.